Herpes Simplex Virus 2 (HSV-2) is highly infectious and prevalent both in the United States and worldwide. Population based data have shown that in the U.S., 17.8% of the general U.S. population has acquired HSV-2 infection. In some demographic groups such as African American women, the seroprevalence approaches 60%. Women possess higher seroprevalence rates than men, and HSV-2 seroprevalence rates in many areas of the world are double that of the U.S. population.
Concomitant with the epidemic of HSV-2 in the U.S. is the increasing prevalence of neonatal HSV-2. An estimated 1,300 cases of neonatal HSV are seen yearly—a higher number of cases than neonatal HIV ever achieved in the U.S. Neonatal HSV, even treated, has a mortality of >15%, and the neurological morbidity among HSV-2 infected infants is an additional 30-50% of surviving cases. Case series indicate that 70% of neonatal HSV cases are related to the acquisition of HSV-1 or HSV-2 by the mother in late pregnancy.
The increasing prevalence of HSV-2 in the adult population has occurred despite the development and widespread use of antiviral therapy for HSV-2. Antecedent HSV-2 increases the risk of HIV infection by 2-3 fold. Data from Rakai, Uganda, show that on a per contact basis the HSV-2 infected person has a 5-7 fold increased rate of HIV-1 acquisition than the HSV-2 seronegative person. Mathematical modeling of the epidemiological data has indicated that from ⅓ to ½ of the cases of HIV-1 in areas of Africa such as Kisumu, Kenya, can be directly attributed to HSV-2. This effect on HIV is higher for HSV-2 than any other sexually transmitted illness (STI). HSV-2/HIV co-infected persons appear to be a major “super spreader” of HIV within their communities. In addition, large scale international studies have shown the ineffectiveness of antiviral therapy of HSV-2 to reduce HIV-1 acquisition and demonstrated the inability of acyclovir to reduce transmission between HIV-1 discordant couples.
The genome of Herpes Simplex Viruses (HSV-1 and HSV-2) contains about 85 open reading frames, such that HSV can generate at least 85 unique proteins. These genes encode 4 major classes of proteins: (1) those associated with the outermost external lipid bilayer of HSV (the envelope), (2) the internal protein coat (the capsid), (3) an intermediate complex connecting the envelope with the capsid coat (the tegument), and (4) proteins responsible for replication and infection.
Examples of envelope proteins include UL1 (gL), UL10 (gM), UL20, UL22, UL27 (gB), UL43, UL44 (gC), UL45, UL49A, UL53 (gK), US4 (gG), US5 (gJ), US6 (gD), US7 (gI), US8 (gE), and US10. Examples of capsid proteins include UL6, UL18, UL19, UL35, and UL38. Tegument proteins include UL11, UL13, UL21, UL36, UL37, UL41, UL45, UL46, UL47, UL48, UL49, US9, and US10. Other HSV proteins include UL2, UL3 UL4, UL5, UL7, UL8, UL9, UL12, UL14, UL15, UL16, UL17, UL23, UL24, UL25, UL26, UL26.5, UL28, UL29, UL30, UL31, UL32, UL33, UL34, UL39, UL40, UL42, UL50, UL51, UL52, UL54, UL55, UL56, US1, US2, US3, US81, US11, US12, ICP0, and ICP4.
Since the envelope (most external portion of an HSV particle) is the first to encounter target cells, much of the early HSV-2 vaccine development work focused on using proteins associated with the envelope as immunogenic agents. In brief, surface and membrane proteins—glycoprotein D (gD), glycoprotein B (gB), glycoprotein H (gH), glycoprotein L (gL)—as single antigens or in combination with or without adjuvants have been tested as possible vaccine antigens. Each was able to stimulate neutralizing antibody titers and “protect” HSV-2 infected animals in challenge models. In humans, all of these vaccines elicited HSV specific neutralizing antibodies among seronegative and HSV-1 seropositive individuals. Neutralizing antibody titers were found to be equal to or 5-10 fold higher than that measured in HSV-2 seropositive individuals.
The most promising candidate was glycoprotein D in which multiple clinical trials were conducted, including a very large Phase III trial. Results from this clinical trial showed that, though circulating neutralizing antibody titers were present and high, only 35% of the seronegative women showed a reduction in HSV-1 acquisition. No benefit was observed in men. These disappointing findings indicate that the stimulation of neutralizing antibodies is insufficient for an effective HSV-2 vaccine. More specifically, these results suggest that immunization with envelope proteins for induction of neutralizing antibodies is inadequate to generate an effective HSV vaccine.
There is a need for an effective HSV vaccine for the public health control of HSV infection.